Rare coding variants in CHRNB2 reduce the likelihood of smoking
Authors: Veera M. Rajagopal, Kyoko Watanabe, Joelle Mbatchou, Ariane Ayer, Peter Quon, Deepika Sharma, Michael D. Kessler, Kavita Praveen, Sahar Gelfman, Neelroop Parikshak, Jacqueline M. Otto, Suying Bao, Shek Man Chim, Elias Pavlopoulos, Andreja Avbersek, Manav Kapoor, Esteban Chen, Marcus B. Jones, Michelle Leblanc, Jonathan Emberson, Rory Collins, Jason Torres, Pablo Kuri Morales, Roberto Tapia-Conyer, Jesus Alegre, Jaime Berumen, Lance J. Adams, Jackie Blank, Dale Bodian, Derek Boris, Adam Buchanan, David J. Carey, Ryan D. Colonie, F. Daniel Davis, Dustin N. Hartzel, Melissa Kelly, H. Lester Kirchner, Joseph B. Leader, David H. Ledbetter, J. Neil Manus, Christa L. Martin, Raghu P. Metpally, Michelle Meyer, Tooraj Mirshahi, Matthew Oetjens, Thomas Nate Person, Christopher Still, Natasha Strande, Amy Sturm, Jen Wagner, Marc Williams, Aris Economides, Andrew Deubler, Katia Karalis, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Katherine Siminovitch, Lyndon J. Mitnaul, Alan Shuldiner, Adolfo Ferrando, Christina Beechert, Caitlin Forsythe, Erin D. Brian, Zhenhua Gu, Michael Lattari, Alexander Lopez, Maria Sotiropoulos, Manasi Pradhan, Kia Manoochehri, Ricardo Schiavo, Raymond Reynoso, Kristy Guevara, Laura M. Cremona, Chenggu Wang, Hang Du, Sarah E. Wolf, Amelia Averitt, Nilanjana Banerjee, Dadong Li, Sameer Malhotra, Justin Mower, Jay Sundaram, Aaron Zhang, Sean Yu, Mudasar Sarwar, Jeffrey C. Staples, Xiaodong Bai, Lance Zhang, Sean O’Keeffe, Andrew Bunyea, Lukas Habegger, Boris Boutkov, Gisu Eom, Alicia Hawes, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan Edelstein, Sujit Gokhale, Alexander Gorovits, Evan K. Maxwell, Ju Guan, George Mitra, Janice Clauer, Mona Nafde, Vrushali Mahajan, Razvan Panea, Koteswararao Makkena, Krishna PawanPunuru, Benjamin Sultan, Sanjay Sreeram, Tommy Polanco, Ayesha Rasool, William J. Salerno, Kathie Sun, Joshua Backman, Anthony Marcketta, Bin Ye, Lauren Gurski, Nan Lin, Jan Revez, Yuxin Zou, Jack Kosmicki, Jonathan Ross, Andrey Ziyatdinov, Eli Stahl, Akropravo Ghosh, Lei Chen, Rujin Wang, Adam Locke, Carlo Sidore, Arden Moscati, Lee Dobbyn, Blair Zhang, Christopher Gillies, Michael Kessler, Maria Suciu, Timothy Thornton, Priyanka Nakka, Sheila Gaynor, Tyler Joseph, Benjamin Geraghty, Anita Pandit, Joseph Herman, Sam Choi, Peter VandeHaar, Liron Ganel, Kuan-Han Wu, Aditeya Pandey, Kathy Burch, Adrian Campos, Scott Vrieze, Sailaja Vedantam, Charles Paulding, Amy Damask, Aysegul Guvenek, George Hindy, None Jan Freudenberg, Jonas Bovijn, Mary Haas, Moeen Riaz, Niek Verweij, Olukayode Sosina, Parsa Akbari, Tanima De, Gannie Tzoneva, Jin He, Silvia Alvarez, Kayode Sosina, Jacqueline Otto, Anna Alkelai, Vijay Kumar, Peter Dombos, Amit Joshi, Sarah Graham, Luanluan Sun, Antoine Baldassari, Jessie Brown, Cristen J. Willer, Arthur Gilly, Hossein Khiabanian, Brian Hobbs, Billy Palmer, Juan Rodriguez-Flores, Jaimee Hernandez, Michelle G. LeBlanc, Jason Mighty, Nirupama Nishtala, Nadia Rana, Jennifer Rico-Varela, Randi Schwartz, Thomas Coleman, Alison Fenney, Jody Hankins, Ruan Cox, Samuel Hart, Alan R. Shuldiner, Suganthi Balasubramanian, Gonçalo R. Abecasis, Hyun M. Kang, Jonathan Marchini, Eli A. Stahl, Eric Jorgenson, Robert Sanchez, Wolfgang Liedtke, Matthew Anderson, Michael Cantor, David Lederer, Aris Baras, Giovanni Coppola
Journal: Nature Genetics (2023)

Abstract Human genetic studies of smoking behavior have been thus far largely limited to common variants. Studying rare coding variants has the potential to identify drug targets. We performed an exome-wide association study of smoking phenotypes in up to 749,459 individuals and discovered a protective association in CHRNB2 , encoding the β2 subunit of the α4β2 nicotine acetylcholine receptor. Rare predicted loss-of-function and likely deleterious missense variants in CHRNB2 in aggregate were associated with a 35% decreased odds for smoking heavily (odds ratio (OR) = 0.65, confidence interval (CI) = 0.56–0.76, P = 1.9 × 10 −8 ). An independent common variant association in the protective direction ( rs2072659 ; OR = 0.96; CI = 0.94–0.98; P = 5.3 × 10 −6 ) was also evident, suggesting an allelic series. Our findings in humans align with decades-old experimental observations in mice that β2 loss abolishes nicotine-mediated neuronal responses and attenuates nicotine self-administration. Our genetic discovery will inspire future drug designs targeting CHRNB2 in the brain for the treatment of nicotine addiction.